The project objective is to significantly improve our understanding of heterogeneous and shared mechanisms in normal aging and Alzheimer?s disease (AD); identify genetic factors that may protect against the age-associated declines in brain resilience and resistance to AD, and validate new candidate genetic targets for AD prevention/treatment using preclinical biomarkers of AD pathology. This objective will be addressed using data collected in twelve large longitudinal and cross-sectional human studies with genetic and phenotypic information on more than half a million individuals in total. Specific Aims: 1. Identify new pleiotropic variants that influence both aging and AD traits, and evaluate their joint impacts on AD risk and survival. Our hypothesis is that pleiotropic SNPs that are associated with multiple phenotypes of aging and AD may have a broad systemic influence on these traits and jointly affect AD risk and longevity. We will select such pleiotropic SNPs, using PheWas approach; evaluate their joint impacts (additive and epistatic) on AD and survival traits; select top results and specify pathways enriched in respective genes; and suggest potential mechanisms connecting these pathways with AD. Pre-clinical validation of the results will be done in Aim 3. Aim 2. Explore shared biological mechanisms between aging and AD, and their genetic heterogeneity, and identify new candidate genetic targets for AD prevention. Our hypothesis is that genes connected in the same pathway relevant to aging and AD will more likely jointly influence relevant phenotypes than genes from different pathways. We will first select sets of candidate genes representing major pathways and processes involved in physiological aging, brain resilience to damage and resistance to AD, based on current evidence from human and experimental studies. Then we will evaluate the collective effects (additive and epistatic) of genes from these pathways on aging and AD traits. Top results will be further validated in Aim 3. Aim 3. Preclinical validation of candidate genetic targets selected in Aims 1, 2, using biomarkers of AD pathology, and further exploration of mechanisms of genetic associations. To further validate sets of genetic variants that together influenced AD risk and/or survival in Aims 1 and 2, we will estimate their joint effects on preclinical biomarkers of AD pathology, such as hippocampal volume, CSF and metabolic (FDG) biomarkers, and metabolomics profiles, considering other covariates. We will also explore causal relationships between the genetic factors found in Aims 1 and 2, and phenotypes of aging and AD, using Mendelian Randomization and related approaches. Results of this project will significantly improve our understanding of the shared and heterogeneous mechanisms of aging and AD, and will help identify protective genetic factors against the age-declines in brain resilience and resistance to AD, and suggest new genetic targets for AD personalized prevention and treatment.